Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-0-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (Hanahan D. J., et al., J. Biol. Chem. 255:5514, 1980). Even before its chemical identification, PAF had been linked to various biological activities and pathways making it one of the important mediators responsible for a variety of physiological processes including activation or coagulation of platelets, pathogenesis of immune complex deposition, smooth muscle contraction, inflammation, pain, edema as well as respiratory, cardiovascular and intravascular alterations. Since these physiological processes are in turn associated with a large group of diseases, for example, inflammatory disease, cardiovascular disorder, asthma, lung edema, and adult respiratory distress syndrome, more and more scientific investigation has been focused on the search of a PAF-antagonist or inhibitor for treating or preventing these common diseases.
The compounds of the present invention are specific PAF-antagonists. They are similar to a subclass of compounds called lignans which characteristically contain two phenylpropyl groups bonded at the .beta.-carbon. Tetrahydrofuran (THF) lignans can exist in six different stereoisomers as shown in Scheme I. ##STR1##
We have been able to prepare all the possible isomers of the tetrahydrofuran lignan analogs with differert substituents and found that exists a conformatior - activity relationship favoring the trans 2,5-diaryltetrahydrofurans.
Accordingly, it is the object of the present invention to prepare the most potent isomers of known or novel tetrahydrofuran derivatives as PAF-antagonists and use them for the treatment of various diseases including prevention of platelet aggregation, hypertension, inflamation, asthma, lung edema, adult respiratory distress syndrome, cardiovascular disorder and other related skeletal-muscular disorders.
Another object of the present invention is to develop processes for the preparation of each and every stereoisomer of the 2,5-diaryltetrahydrofuran analogs.
A further otject of the present invention is to provide acceptable pharmaceutical compositions containing one or more of the tetrahydrofuran derivatives and/or analogs as the active ingredient. As PAF-antagonists, these novel compositions should be effective in the treatment of various skeletal-muscular related diseases.
Finally, it is the ultimate object of this invention to provide a method of treatment comprising the administration of a therapeutically sufficient amount of these PAF antagonists to a patient suffering from various skeletal-muscular disorders including inflammation, e.g., osteoarthritis, rheumatoid arthritis and gout, hypertension, asthma, pain, lung edema, or adult respiratory distress syndrome or cardiovascular disorder.